On the Difficulty Predicting Word Recognition Performance After Cochlear Implantation.

HYPOTHESIS: Preimplantation word scores cannot reliably predict postimplantation outcomes. BACKGROUND: To date, there is no model based on preoperative data that can reliably predict the postoperative outcomes of cochlear implantation in the postlingually deafened adult patient. METHODS: In a group of 228 patients who received a cochlear implant between 2002 and 2021, we tested the predictive power of nine variables (age, etiology, sex, laterality of implantation, preimplantation thresholds and word scores, as well as the design, insertion approach, and angular insertion depth of the electrode array) on postimplantation outcomes. Results of multivariable linear regression analyses were then interpreted in light of data obtained from histopathological analyses of human temporal bones. RESULTS: Age and etiology were the only significant predictors of postimplantation outcomes. In agreement with many investigations, preimplantation word scores failed to significantly predict postimplantation outcomes. Analysis of temporal bone histopathology suggests that neuronal survival must fall below 40% before word scores in quiet begin to drop. Scores fall steeply with further neurodegeneration, such that only 20% survival can support acoustically driven word scores of 50%. Because almost all cochlear implant implantees have at least 20% of their spiral ganglion neurons (SGNs) surviving, it is expected that most cochlear implant users on average should improve to at least 50% word recognition score, as we observed, even if their preimplantation score was near zero as a result of widespread hair cell damage and the fact that ~50% of their SGNs have likely lost their peripheral axons. These "disconnected" SGNs would not contribute to acoustic hearing but likely remain electrically excitable. CONCLUSION: The relationship between preimplantation word scores and data describing the survival of SGNs in humans can explain why preimplantation word scores obtained in unaided conditions fail to predict postimplantation outcomes.

Evidence of cochlear neural degeneration in normal-hearing subjects with tinnitus.

Tinnitus, reduced sound-level tolerance, and difficulties hearing in noisy environments are the most common complaints associated with sensorineural hearing loss in adult populations. This study aims to clarify if cochlear neural degeneration estimated in a large pool of participants with normal audiograms is associated with self-report of tinnitus using a test battery probing the different stages of the auditory processing from hair cell responses to the auditory reflexes of the brainstem. Self-report of chronic tinnitus was significantly associated with (1) reduced cochlear nerve responses, (2) weaker middle-ear muscle reflexes, (3) stronger medial olivocochlear efferent reflexes and (4) hyperactivity in the central auditory pathways. These results support the model of tinnitus generation whereby decreased neural activity from a damaged cochlea can elicit hyperactivity from decreased inhibition in the central nervous system.

Isolating auditory-nerve contributions to electrocochleography by high-pass filtering: A better biomarker for cochlear nerve degeneration?

In search of biomarkers for cochlear neural degeneration (CND) in electrocochleography from humans with normal thresholds, we high-pass and low-pass filtered the responses to separate contributions of auditory-nerve action potentials (N1) from hair-cell summating potentials (SP). The new N1 measure is better correlated with performance on difficult word-recognition tasks used as a proxy for CND. Furthermore, the paradoxical correlation between larger SPs and worse word scores, observed with classic electrocochleographic analysis, disappears with the new metric. Classic SP is simultaneous with and opposite in phase to an early neural contribution, and filtering separates the sources to eliminate this interference.

Estimated cochlear neural degeneration is associated with loudness hypersensitivity in individuals with normal audiograms.

In animal models, cochlear neural degeneration (CND) is associated with excess central gain and hyperacusis, but a compelling link between reduced cochlear neural inputs and heightened loudness perception in humans remains elusive. The present study examined whether greater estimated cochlear neural degeneration (eCND) in human participants with normal hearing thresholds is associated with heightened loudness perception and sound aversion. Results demonstrated that loudness perception was heightened in ears with greater eCND and in subjects who self-report loudness aversion via a hyperacusis questionnaire. These findings suggest that CND may be a potential trigger for loudness hypersensitivity.

Predicting neural deficits in sensorineural hearing loss from word recognition scores.

The current gold standard of clinical hearing assessment includes a pure-tone audiogram combined with a word recognition task. This retrospective study tests the hypothesis that deficits in word recognition that cannot be explained by loss in audibility or cognition may reflect underlying cochlear nerve degeneration (CND). We collected the audiological data of nearly 96,000 ears from patients with normal hearing, conductive hearing loss (CHL) and a variety of sensorineural etiologies including (1) age-related hearing loss (ARHL); (2) neuropathy related to vestibular schwannoma or neurofibromatosis of type 2; (3) Ménière's disease; (4) sudden sensorineural hearing loss (SSNHL), (5) exposure to ototoxic drugs (carboplatin and/or cisplatin, vancomycin or gentamicin) or (6) noise damage including those with a 4-kHz "noise notch" or reporting occupational or recreational noise exposure. Word recognition was scored using CID W-22 monosyllabic word lists. The Articulation Index was used to predict the speech intelligibility curve using a transfer function for CID W-22. The level at which maximal intelligibility was predicted was used as presentation level (70 dB HL minimum). Word scores decreased dramatically with age and thresholds in all groups with SNHL etiologies, but relatively little in the conductive hearing loss group. Discrepancies between measured and predicted word scores were largest in patients with neuropathy, Ménière's disease and SSNHL, intermediate in the noise-damage and ototoxic drug groups, and smallest in the ARHL group. In the CHL group, the measured and predicted word scores were very similar. Since word-score predictions assume that audiometric losses can be compensated by increasing stimulus level, their accuracy in predicting word score for CHL patients is unsurprising. The lack of a strong age effect on word scores in CHL shows that cognitive decline is not a major factor in this test. Amongst the possible contributions to word score discrepancies, CND is a prime candidate: it should worsen intelligibility without affecting thresholds and has been documented in human temporal bones with SNHL. Comparing the audiological trends observed here with the existing histopathological literature supports the notion that word score discrepancies may be a useful CND metric.

Preserving Wideband Tympanometry Information With Artifact Mitigation.

OBJECTIVE: Absorbance measured using wideband tympanometry (WBT) has been shown to be sensitive to changes in middle and inner ear mechanics, with potential to diagnose various mechanical ear pathologies. However, artifacts in absorbance due to measurement noise can obscure information related to pathologies and increase intermeasurement variability. Published reports frequently present absorbance that has undergone smoothing to minimize artifact; however, smoothing changes the true absorbance and can destroy important narrow-band characteristics such as peaks and notches at different frequencies. Because these characteristics can be unique to specific pathologies, preserving them is important for diagnostic purposes. Here, we identify the cause of artifacts in absorbance and develop a technique to mitigate artifacts while preserving the underlying WBT information. DESIGN: A newly developed Research Platform for the Interacoustics Titan device allowed us to study raw microphone recordings and corresponding absorbances obtained by WBT measurements. We investigated WBT measurements from normal hearing ears and ears with middle and inner ear pathologies for the presence of artifact and noise. Furthermore, it was used to develop an artifact mitigation procedure and to evaluate its effectiveness in mitigating artifacts without distorting the true WBT information. RESULTS: We observed various types of noise that can plague WBT measurements and that contribute to artifacts in computed absorbances, particularly intermittent low-frequency noise. We developed an artifact mitigation procedure that incorporates a high-pass filter and a Tukey window. This artifact mitigation resolved the artifacts from low-frequency noise while preserving characteristics in absorbance in both normal hearing ears and ears with pathology. Furthermore, the artifact mitigation reduced intermeasurement variability. CONCLUSIONS: Unlike smoothing algorithms used in the past, our artifact mitigation specifically removes artifacts caused by noise. It does not change frequency response characteristics, such as narrow-band peaks and notches in absorbance at different frequencies that can be important for diagnosis. Also, by reducing intermeasurement variability, the artifact mitigation can improve the test-retest reliability of these measurements.

The summating potential in human electrocochleography: Gaussian models and Fourier analysis.

In recent electrocochleographic studies, the amplitude of the summating potential (SP) was an important predictor of performance on word-recognition in difficult listening environments among normal-hearing listeners; paradoxically the SP was largest in those with the worst scores. SP has traditionally been extracted by visual inspection, a technique prone to subjectivity and error. Here, we assess the utility of a fitting algorithm [Kamerer, Neely, and Rasetshwane (2020). J Acoust Soc Am. 147, 25-31] using a summed-Gaussian model to objectify and improve SP identification. Results show that SPs extracted by visual inspection correlate better with word scores than those from the model fits. We also use fast Fourier transform to decompose these evoked responses into their spectral components to gain insight into the cellular generators of SP. We find a component at 310 Hz associated with word-identification tasks that correlates with SP amplitude. This component is absent in patients with genetic mutations affecting synaptic transmission and may reflect a contribution from excitatory post-synaptic potentials in auditory nerve fibers.

Envelope following responses predict speech-in-noise performance in normal-hearing listeners.

Permanent threshold elevation after noise exposure or aging is caused by loss of sensory cells; however, animal studies show that hair cell loss is often preceded by degeneration of the synapses between sensory cells and auditory nerve fibers. Silencing these neurons is likely to degrade auditory processing and may contribute to difficulties understanding speech in noisy backgrounds. Reduction of suprathreshold ABR amplitudes can be used to quantify synaptopathy in inbred mice. However, ABR amplitudes are highly variable in humans, and thus more challenging to use. Since noise-induced neuropathy preferentially targets fibers with high thresholds and low spontaneous rate and because phase locking to temporal envelopes is particularly strong in these fibers, measuring envelope following responses (EFRs) might be a more robust measure of cochlear synaptopathy. A recent auditory model further suggests that modulation of carrier tones with rectangular envelopes should be less sensitive to cochlear amplifier dysfunction and, therefore, a better metric of cochlear neural damage than sinusoidal amplitude modulation. In this study, we measure performance scores on a variety of difficult word-recognition tasks among listeners with normal audiograms and assess correlations with EFR magnitudes to rectangular versus sinusoidal modulation. Higher harmonics of EFR magnitudes evoked by a rectangular-envelope stimulus were significantly correlated with word scores, whereas those evoked by sinusoidally modulated tones did not. These results support previous reports that individual differences in synaptopathy may be a source of speech recognition variability despite the presence of normal thresholds at standard audiometric frequencies.NEW & NOTEWORTHY Recent studies suggest that millions of people may be at risk of permanent impairment from cochlear synaptopathy, the age-related and noise-induced degeneration of neural connections in the inner ear. This study examines electrophysiological responses to stimuli designed to improve detection of neural damage in subjects with normal hearing sensitivity. The resultant correlations with word recognition performance are consistent with a contribution of cochlear neural damage to deficits in hearing in noise abilities.

Idiopathic Sudden Sensorineural Hearing Loss: Speech Intelligibility Deficits Following Threshold Recovery.

OBJECTIVES: This retrospective study tests the hypothesis that patients who have recovered from idiopathic sudden sensorineural hearing loss (SSNHL) show deficits in word recognition tasks that cannot be entirely explained by a loss in audibility. DESIGN: We reviewed the audiologic profile of 166 patients presenting with a unilateral SSNHL. Hearing loss severity, degree of threshold recovery, residual hearing loss, and word recognition performance were considered as outcome variables. Age, route of treatment, delay between SSNHL onset and treatment, and audiogram configuration were considered as predictor variables. RESULTS: Severity, residual hearing loss, and recovery were highly variable across patients. While age and onset-treatment delay could not account for the severity, residual hearing loss and recovery in thresholds, configuration of the SSNHL and overall inner ear status as measured by thresholds on the contralateral ear were predictive of threshold recovery. Speech recognition performance was significantly poorer than predicted by the speech intelligibility curve derived from the patient's audiogram. CONCLUSIONS: SSNHL is associated with (1) changes in thresholds that are consistent with ischemia and (2) speech intelligibility deficits that cannot be entirely explained by a change in hearing sensitivity.

Electrophysiological markers of cochlear function correlate with hearing-in-noise performance among audiometrically normal subjects.

Hearing loss caused by noise exposure, ototoxic drugs, or aging results from the loss of sensory cells, as reflected in audiometric threshold elevation. Animal studies show that loss of hair cells can be preceded by loss of auditory-nerve peripheral synapses, which likely degrades auditory processing. While this condition, known as cochlear synaptopathy, can be diagnosed in mice by a reduction of suprathreshold cochlear neural responses, its diagnosis in humans remains challenging. To look for evidence of cochlear nerve damage in normal hearing subjects, we measured their word recognition performance in difficult listening environments and compared it to cochlear function as assessed by otoacoustic emissions and click-evoked electrocochleography. Several electrocochleographic markers were correlated with word scores, whereas distortion product otoacoustic emissions were not. Specifically, the summating potential (SP) was larger and the cochlear nerve action potential (AP) was smaller in those with the worst word scores. Adding a forward masker or increasing stimulus rate reduced SP in the worst performers, suggesting that this potential includes postsynaptic components as well as hair cell receptor potentials. Results suggests that some of the variance in word scores among listeners with normal audiometric threshold arises from cochlear neural damage.NEW & NOTEWORTHY Recent animal studies suggest that millions of people may be at risk of permanent impairment from cochlear synaptopathy, the age-related and noise-induced degeneration of neural connections in the inner ear that "hides" behind a normal audiogram. This study examines electrophysiological responses to clicks in a large cohort of subjects with normal hearing sensitivity. The resultant correlations with word recognition performance are consistent with an important contribution cochlear neural damage to deficits in hearing in noise abilities.

Chronic Conductive Hearing Loss Is Associated With Speech Intelligibility Deficits in Patients With Normal Bone Conduction Thresholds.

OBJECTIVES: The main objective of this study is to determine whether chronic sound deprivation leads to poorer speech discrimination in humans. DESIGN: We reviewed the audiologic profile of 240 patients presenting normal and symmetrical bone conduction thresholds bilaterally, associated with either an acute or chronic unilateral conductive hearing loss of different etiologies. RESULTS: Patients with chronic conductive impairment and a moderate, to moderately severe, hearing loss had lower speech recognition scores on the side of the pathology when compared with the healthy side. The degree of impairment was significantly correlated with the speech recognition performance, particularly in patients with a congenital malformation. Speech recognition scores were not significantly altered when the conductive impairment was acute or mild. CONCLUSIONS: This retrospective study shows that chronic conductive hearing loss was associated with speech intelligibility deficits in patients with normal bone conduction thresholds. These results are as predicted by a recent animal study showing that prolonged, adult-onset conductive hearing loss causes cochlear synaptopathy.

Middle Ear Muscle Reflex and Word Recognition in "Normal-Hearing" Adults: Evidence for Cochlear Synaptopathy?

OBJECTIVES: Permanent threshold elevation after noise exposure, ototoxic drugs, or aging is caused by loss of sensory cells; however, animal studies show that hair cell loss is often preceded by degeneration of synapses between sensory cells and auditory nerve fibers. The silencing of these neurons, especially those with high thresholds and low spontaneous rates, degrades auditory processing and may contribute to difficulties in understanding speech in noise. Although cochlear synaptopathy can be diagnosed in animals by measuring suprathreshold auditory brainstem responses, its diagnosis in humans remains a challenge. In mice, cochlear synaptopathy is also correlated with measures of middle ear muscle (MEM) reflex strength, possibly because the missing high-threshold neurons are important drivers of this reflex. The authors hypothesized that measures of the MEM reflex might be better than other assays of peripheral function in predicting difficulties hearing in difficult listening environments in human subjects. DESIGN: The authors recruited 165 normal-hearing healthy subjects, between 18 and 63 years of age, with no history of ear or hearing problems, no history of neurologic disorders, and unremarkable otoscopic examinations. Word recognition in quiet and in difficult listening situations was measured in four ways: using isolated words from the Northwestern University auditory test number six corpus with either (a) 0 dB signal to noise, (b) 45% time compression with reverberation, or (c) 65% time compression with reverberation, and (d) with a modified version of the QuickSIN. Audiometric thresholds were assessed at standard and extended high frequencies. Outer hair cell function was assessed by distortion product otoacoustic emissions (DPOAEs). Middle ear function and reflexes were assessed using three methods: the acoustic reflex threshold as measured clinically, wideband tympanometry as measured clinically, and a custom wideband method that uses a pair of click probes flanking an ipsilateral noise elicitor. Other aspects of peripheral auditory function were assessed by measuring click-evoked gross potentials, that is, summating potential (SP) and action potential (AP) from ear canal electrodes. RESULTS: After adjusting for age and sex, word recognition scores were uncorrelated with audiometric or DPOAE thresholds, at either standard or extended high frequencies. MEM reflex thresholds were significantly correlated with scores on isolated word recognition, but not with the modified version of the QuickSIN. The highest pairwise correlations were seen using the custom assay. AP measures were correlated with some of the word scores, but not as highly as seen for the MEM custom assay, and only if amplitude was measured from SP peak to AP peak, rather than baseline to AP peak. The highest pairwise correlations with word scores, on all four tests, were seen with the SP/AP ratio, followed closely by SP itself. When all predictor variables were combined in a stepwise multivariate regression, SP/AP dominated models for all four word score outcomes. MEM measures only enhanced the adjusted r values for the 45% time compression test. The only other predictors that enhanced model performance (and only for two outcome measures) were measures of interaural threshold asymmetry. CONCLUSIONS: Results suggest that, among normal-hearing subjects, there is a significant peripheral contribution to diminished hearing performance in difficult listening environments that is not captured by either threshold audiometry or DPOAEs. The significant univariate correlations between word scores and either SP/AP, SP, MEM reflex thresholds, or AP amplitudes (in that order) are consistent with a type of primary neural degeneration. However, interpretation is clouded by uncertainty as to the mix of pre- and postsynaptic contributions to the click-evoked SP. None of the assays presented here has the sensitivity to diagnose neural degeneration on a case-by-case basis; however, these tests may be useful in longitudinal studies to track accumulation of neural degeneration in individual subjects.

Effects of cochlear synaptopathy on middle-ear muscle reflexes in unanesthetized mice.

Cochlear synaptopathy, i.e. the loss of auditory-nerve connections with cochlear hair cells, is seen in aging, noise damage, and other types of acquired sensorineural hearing loss. Because the subset of auditory-nerve fibers with high thresholds and low spontaneous rates (SRs) is disproportionately affected, audiometric thresholds are relatively insensitive to this primary neural degeneration. Although suprathreshold amplitudes of wave I of the auditory brainstem response (ABR) are attenuated in synaptopathic mice, there is not yet a robust diagnostic in humans. The middle-ear muscle reflex (MEMR) might be a sensitive metric (Valero et al., 2016), because low-SR fibers may be important drivers of the MEMR (Liberman and Kiang, 1984; Kobler et al., 1992). Here, to test the hypothesis that narrowband reflex elicitors can identify synaptopathic cochlear regions, we measured reflex growth functions in unanesthetized mice with varying degrees of noise-induced synaptopathy and in unexposed controls. To separate effects of the MEMR from those of the medial olivocochlear reflex, the other sound-evoked cochlear feedback loop, we used a mutant mouse strain with deletion of the acetylcholine receptor required for olivocochlear function. We demonstrate that the MEMR is normal when activated from non-synaptopathic cochlear regions, is greatly weakened in synaptopathic regions, and is a more sensitive indicator of moderate synaptopathy than the suprathreshold amplitude of ABR wave I.

A Gain-of-Function Mutation in the α9 Nicotinic Acetylcholine Receptor Alters Medial Olivocochlear Efferent Short-Term Synaptic Plasticity.

Gain control of the auditory system operates at multiple levels. Cholinergic medial olivocochlear (MOC) fibers originate in the brainstem and make synaptic contacts at the base of the outer hair cells (OHCs), the final targets of several feedback loops from the periphery and higher-processing centers. Efferent activation inhibits OHC active amplification within the mammalian cochlea, through the activation of a calcium-permeable α9α10 ionotropic cholinergic nicotinic receptor (nAChR), functionally coupled to calcium activated SK2 potassium channels. Correct operation of this feedback requires careful matching of acoustic input with the strength of cochlear inhibition (Galambos, 1956; Wiederhold and Kiang, 1970; Gifford and Guinan, 1987), which is driven by the rate of MOC activity and short-term facilitation at the MOC-OHC synapse (Ballestero et al., 2011; Katz and Elgoyhen, 2014). The present work shows (in mice of either sex) that a mutation in the α9α10 nAChR with increased duration of channel gating (Taranda et al., 2009) greatly elongates hair cell-evoked IPSCs and Ca2+ signals. Interestingly, MOC-OHC synapses of L9'T mice presented reduced quantum content and increased presynaptic facilitation. These phenotypic changes lead to enhanced and sustained synaptic responses and OHC hyperpolarization upon high-frequency stimulation of MOC terminals. At the cochlear physiology level these changes were matched by a longer time course of efferent MOC suppression. This indicates that the properties of the MOC-OHC synapse directly determine the efficacy of the MOC feedback to the cochlea being a main player in the "gain control" of the auditory periphery.SIGNIFICANCE STATEMENT Plasticity can involve reciprocal signaling across chemical synapses. An opportunity to study this phenomenon occurs in the mammalian cochlea whose sensitivity is regulated by efferent olivocochlear neurons. These release acetylcholine to inhibit sensory hair cells. A point mutation in the hair cell's acetylcholine receptor that leads to increased gating of the receptor greatly elongates IPSCs. Interestingly, efferent terminals from mutant mice present a reduced resting release probability. However, upon high-frequency stimulation transmitter release facilitates strongly to produce stronger and far longer-lasting inhibition of cochlear function. Thus, central neuronal feedback on cochlear hair cells provides an opportunity to define plasticity mechanisms in cholinergic synapses other than the highly studied neuromuscular junction.

Toward a Differential Diagnosis of Hidden Hearing Loss in Humans.

Recent work suggests that hair cells are not the most vulnerable elements in the inner ear; rather, it is the synapses between hair cells and cochlear nerve terminals that degenerate first in the aging or noise-exposed ear. This primary neural degeneration does not affect hearing thresholds, but likely contributes to problems understanding speech in difficult listening environments, and may be important in the generation of tinnitus and/or hyperacusis. To look for signs of cochlear synaptopathy in humans, we recruited college students and divided them into low-risk and high-risk groups based on self-report of noise exposure and use of hearing protection. Cochlear function was assessed by otoacoustic emissions and click-evoked electrocochleography; hearing was assessed by behavioral audiometry and word recognition with or without noise or time compression and reverberation. Both groups had normal thresholds at standard audiometric frequencies, however, the high-risk group showed significant threshold elevation at high frequencies (10-16 kHz), consistent with early stages of noise damage. Electrocochleography showed a significant difference in the ratio between the waveform peaks generated by hair cells (Summating Potential; SP) vs. cochlear neurons (Action Potential; AP), i.e. the SP/AP ratio, consistent with selective neural loss. The high-risk group also showed significantly poorer performance on word recognition in noise or with time compression and reverberation, and reported heightened reactions to sound consistent with hyperacusis. These results suggest that the SP/AP ratio may be useful in the diagnosis of "hidden hearing loss" and that, as suggested by animal models, the noise-induced loss of cochlear nerve synapses leads to deficits in hearing abilities in difficult listening situations, despite the presence of normal thresholds at standard audiometric frequencies.

Perinatal thiamine deficiency causes cochlear innervation abnormalities in mice.

Neonatal thiamine deficiency can cause auditory neuropathy in humans. To probe the underlying cochlear pathology, mice were maintained on a thiamine-free or low-thiamine diet during fetal development or early postnatal life. At postnatal ages from 18 days to 22 wks, cochlear function was tested and cochlear histopathology analyzed by plastic sections and cochlear epithelial whole-mounts immunostained for neuronal and synaptic markers. Although none of the thiamine-deprivation protocols resulted in any loss of hair cells or any obvious abnormalities in the non-sensory structures of the cochlear duct, all the experimental groups showed significant anomalies in the afferent or efferent innervation. Afferent synaptic counts in the inner and outer hair cell areas were reduced, as was the efferent innervation density in both the outer and inner hair cell areas. As expected for primary neural degeneration, the thresholds for distortion product otoacoustic emissions were not affected, and as expected for subtotal hair cell de-afferentation, the suprathreshold amplitudes of auditory brainstem responses were more affected than the response thresholds. We conclude that the auditory neuropathy from thiamine deprivation could be produced by loss of inner hair cell synapses.

Oncomodulin, an EF-Hand Ca2+ Buffer, Is Critical for Maintaining Cochlear Function in Mice.

Oncomodulin (Ocm), a member of the parvalbumin family of calcium binding proteins, is expressed predominantly by cochlear outer hair cells in subcellular regions associated with either mechanoelectric transduction or electromotility. Targeted deletion of Ocm caused progressive cochlear dysfunction. Although sound-evoked responses are normal at 1 month, by 4 months, mutants show only minimal distortion product otoacoustic emissions and 70-80 dB threshold shifts in auditory brainstem responses. Thus, Ocm is not critical for cochlear development but does play an essential role for cochlear function in the adult mouse. SIGNIFICANCE STATEMENT: Numerous proteins act as buffers, sensors, or pumps to control calcium levels in cochlear hair cells. In the inner ear, EF-hand calcium buffers may play a significant role in hair cell function but have been very difficult to study. Unlike other reports of genetic disruption of EF-hand calcium buffers, deletion of oncomodulin (Ocm), which is predominately found in outer hair cells, leads to a progressive hearing loss after 1 month, suggesting that Ocm critically protects hearing in the mature ear.

Chronic Conductive Hearing Loss Leads to Cochlear Degeneration.

Synapses between cochlear nerve terminals and hair cells are the most vulnerable elements in the inner ear in both noise-induced and age-related hearing loss, and this neuropathy is exacerbated in the absence of efferent feedback from the olivocochlear bundle. If age-related loss is dominated by a lifetime of exposure to environmental sounds, reduction of acoustic drive to the inner ear might improve cochlear preservation throughout life. To test this, we removed the tympanic membrane unilaterally in one group of young adult mice, removed the olivocochlear bundle in another group and compared their cochlear function and innervation to age-matched controls one year later. Results showed that tympanic membrane removal, and the associated threshold elevation, was counterproductive: cochlear efferent innervation was dramatically reduced, especially the lateral olivocochlear terminals to the inner hair cell area, and there was a corresponding reduction in the number of cochlear nerve synapses. This loss led to a decrease in the amplitude of the suprathreshold cochlear neural responses. Similar results were seen in two cases with conductive hearing loss due to chronic otitis media. Outer hair cell death was increased only in ears lacking medial olivocochlear innervation following olivocochlear bundle cuts. Results suggest the novel ideas that 1) the olivocochlear efferent pathway has a dramatic use-dependent plasticity even in the adult ear and 2) a component of the lingering auditory processing disorder seen in humans after persistent middle-ear infections is cochlear in origin.

Olivocochlear innervation maintains the normal modiolar-pillar and habenular-cuticular gradients in cochlear synaptic morphology.

Morphological studies of inner hair cell (IHC) synapses with cochlear nerve terminals have suggested that high- and low-threshold fibers differ in the sizes of their pre- and postsynaptic elements as well as the position of their synapses around the hair cell circumference. Here, using high-power confocal microscopy, we measured sizes and spatial positions of presynaptic ribbons, postsynaptic glutamate receptor (GluR) patches, and olivocochlear efferent terminals at eight locations along the cochlear spiral in normal and surgically de-efferented mice. Results confirm a prior report suggesting a modiolar > pillar gradient in ribbon size and a complementary pillar > modiolar gradient in GluR-patch size. We document a novel habenular < cuticular gradient in GluR patch size and a complementary cuticular < habenular gradient in olivocochlear innervation density. All spatial gradients in synaptic elements collapse after cochlear de-efferentation, suggesting a major role of olivocochlear efferents in maintaining functional heterogeneity among cochlear nerve fibers. Our spatial analysis also suggests that adjacent IHCs may contain a different synaptic mix, depending on whether their tilt in the radial plane places their synaptic pole closer to the pillar cells or to the modiolus.